RU2447892C2 - Use of rks inhibitors in diabetes related complications - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine. 1. Using 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione or its pharmaceutically acceptable salts for preparing a drug for treating, preventing or arresting the developing diabetes-related complications - nephropathy, neuropathy or cardiomyopathy. The method of treating or preventing diabetic nephropathy, neuropathy or cardiomyopathy, or arresting the development consisting in introducing an effective amount of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione, or its pharmaceutically acceptable salts in a subject in need thereof. A pharmaceutical composition for treating or preventing the diabetes-related complications contains 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione or its pharmaceutically acceptable salts mixed with one or more pharmaceutically acceptable diluents or carriers wherein the complication is specified in nephropathy, neuropathy or cardiomyopathy. The pharmaceutical composition contains a) a first agent which is specified in 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione or its pharmaceutically acceptable salts, and b) at least one active ingredient which is specified in a group consisting of one compound increasing HDL level, a δ-PPAR compound, a non-glitazone γ-PPAR agonist, an antihypertensive agent, a cholesterol absorption modulator, an apo-A1 analogue or mimetic, a rennin inhibitor, a thrombin inhibitor, an aldosterone inhibitor, a GLP-1 agonist, a glucagon receptor antagonist, a cannabinoid receptor 1 antagonist, an antiobesity agent, a thrombocyte aggregation inhibitor, a PPAR agonist, a prosclerotic growth factor or their pharmaceutically acceptable salts. The method of treating or preventing diabetes or the diabetes-related complications, or arresting the development which consists in the combined introduction e.g. simultaneously or sequentially, of the therapeutically effective amount of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione or its pharmaceutically acceptable salts, and the second drug into the subject in need thereof wherein the second drug is specified in a group consisting of a compound increasing HDL level, an antidiabetic agent, an antihypertensive agent, a cholesterol absorption modulator, an apo-A1 analogue or mimetic, a rennin inhibitor, a thrombin inhibitor, an aldosterone inhibitor, a GLP-1 agonist, a glucagon receptor antagonist, a cannabinoid receptor 1 antagonist, an antiobesity agent, a thrombocyte aggregation inhibitor, a PPAR agonist, a DPP-IV inhibitor, a prosclerotic growth factor or their pharmaceutically acceptable salts.

EFFECT: group of invention provides higher clinical and preventative effectiveness, delayed development of the diabetes-related complications.

8 cl

Description

The present invention provides a new use of a PKC inhibitor in the treatment or prevention of diabetic disorders or complications such as nephropathy and cardiomyopathy.

Cardiac and renal disorders in diabetes are the main causes of mortality and morbidity, however, the basic processes in the cells that accelerate their development remain unexplored. The initial pathological change is believed to be caused by metabolic effects, such as hyperglycemia, leading to adaptive changes in hemodynamic processes, which are accompanied by increased production of growth factors and pro-inflammatory mediators, which leads to inflammation, hypoxia and increased extracellular matrix deposition (ECM).

Diabetic nephropathy is characterized by progressive glomerulosclerosis and tubulointerstitial fibrosis, which are accompanied by proteinuria and a decrease in glomerular filtration rate (GFR), which leads to the final stage of renal failure. Diabetic cardiomyopathy in the early stages is characterized by an abnormal diastolic function, accompanied by minor anomalies of systolic function, which is associated with a decreased function of longitudinal fibers. Histological studies of the heart tissue of patients diagnosed with diabetes indicate increased deposits of the extracellular matrix, mainly fibrillar collagen, and myocardial hypertrophy.

Despite the numerous methods for treating or preventing diabetes and its complications, most diabetic patients have a progression of nephropathy and cardiomyopathy and, therefore, there is a need to develop an effective and safe treatment for these complications.

It has surprisingly been found in the present invention that the protein kinase C (PKC) inhibitors described herein can be used to profile or treat diabetic disorders or complications, especially disorders or complications caused by diabetes mellitus, such as diabetic nephropathy and cardiomyopathy.

The present invention provides the use of PKC inhibitors for the prevention, treatment or retardation of the development of diabetic disorders or complications such as nephropathy, cardiomyopathy or neuropathy, wherein the PKC inhibitors are selected from the group consisting of 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione (compound A), 3- (1H-indol-3-yl) -4- [2- (piperazin- 1-yl) quinazolin-4-yl] pyrrole-2,5-dione (compound B) and 3- [3- (4,7-diazaspiro [2.5] oct-7-yl) isoquinolin-1-yl] -4 - (7-methyl-1H-indol-3-yl) pyrrole-2,5-dione (compound C).

According to the present invention, compounds A, B and C are used in the form of free bases or in the form of pharmaceutically acceptable salts.

Most preferred is compound A, and even more preferred is acetate of compound A.

Compounds A, B and C are known and methods for their preparation are described, for example, in US Pat. No. 6,645,970 or EP 1 490 355 A1. Salts of compounds A, B and C are prepared according to standard procedures and exhibit similar activity compared to the activity of free compounds.

In some embodiments, the present invention also provides:

1. A method of treating, preventing or slowing the development of diabetes complications, as described in this context, the method comprising administering to a patient suffering from these complications a therapeutically effective amount of compound A, B, C or their salts, the most preferred being compound A or its acetate.

The term "complications caused by diabetes", used in this context, means, without limitation, hyperglycemia, hyperinsulinemia, insulin resistance, impaired glucose metabolism, impaired insulin tolerance (IGT), impaired fasting plasma glucose, obesity, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, diabetic cardiomyopathy and Syndrome X, as well as the final stage of renal disease.

The present invention preferably provides a method of treating, preventing or slowing the development of complications caused by diabetes, which method comprises administering to a patient suffering from said complications a therapeutically effective amount of Compound A or a salt thereof, for example its acetate, wherein the complications caused by diabetes are described in given context.

For example, the present invention provides a method for treating, preventing, or slowing the development of diabetic nephropathy, diabetic cardiomyopathy, or diabetic neuropathy, preferably diabetic nephropathy, which comprises administering to a patient suffering from these complications a therapeutically effective amount of compound A, compound B or a salt thereof, for example compound A or its salt, for example compound A or its acetate.

In another embodiment, the present invention provides a method of treating, preventing or slowing the development of hyperglycemia, hyperinsulinemia, insulin resistance, glomerulosclerosis, diabetic cardiomyopathy and end-stage renal disease, which consists in administering to a patient suffering from these complications a therapeutically effective amount of compound C or its salts, for example its acetate.

In yet another aspect of the present invention, there is provided:

2. Compound A, compound B, compound C or their pharmaceutically acceptable salts for use according to the method according to claim 1,

3. Compound A, compound B, compound C or their pharmaceutically acceptable salts for use in the preparation of a pharmaceutical composition intended for use according to the method according to claim 1,

4. The pharmaceutical composition intended for use according to the method according to claim 1, comprising compound A, compound B, compound C or their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable diluents or carriers.

In a preferred embodiment, it is proposed the use of compound A in free form or in the form of a pharmaceutically acceptable salt, for example in the form of its acetate, for the treatment or prevention of complications caused by diabetes, as described above, for example, diabetic nephropathy, diabetic neuropathy or diabetic cardiomyopathy, preferably diabetic nephropathy.

In another preferred embodiment, it is proposed the use of compound C in free form or in the form of a pharmaceutically acceptable salt, for example in the form of its acetate, for the treatment or prevention of diabetic cardiomyopathy.

The usefulness of compound A, B or C for the treatment of complications caused by diabetes, as described in this context, can be demonstrated both using model animals and in clinical trials, for example, according to the methods described in this context.

A. The binding affinity of compounds A, B, and C for individual human PKC receptors can be evaluated by PKC analysis. The specified analysis is carried out according to standard methods (for example, as described in the article D.Geiges and others, Biochem. Pharmacol., T.53, pp. 865-875 (1997)), for example, as described in patent EP 1337527 A1, the content which in relation to the analysis of protein kinase C is included in this description by reference.

B. In vivo assay

Ren-2 rats (e.g., as described in D.J. Kelly et al., Kidney Int., V. 54, pp. 343-352 (1998))

The effects of Compound A, B, or C on diabetes-related complications were investigated using transgenic rats (mRen-2) 27 (Ren-2 rats), which are a model of hypertension and many other structural and functional characteristics of diabetic human nephropathy, causing diabetes streptozotocin, which led to the development of a progressive disease with many structural, functional and molecular characteristics of diabetic human nephropathy. The development of this disease is associated with an increase in the level of renal and cardiac growth factors and extracellular matrix deposits.

The effect of the compounds of the present invention on diabetic nephropathy can be evaluated in a Ren-2 rat model as described in D.J. Kelley et al., Diabetes, Vol. 52, pp. 512-518 (February 2003). Diabetes is caused by an injection of streptozotocin at a dose of 55 mg / kg. All rats with diabetes were injected with insulin (human isofan) at a dose of 2 units / day to increase body weight and reduce mortality. The analysis period was 16 weeks for Ren-2 rats in the study of progressive renal and cardiac diseases. Rats were randomized to the following groups:

Group 1: non-diabetic rats Ren-2, the drug was not administered

Group 2: non-diabetic rats Ren-2, connection C

Group 3: non-diabetic rats Ren-2, connection And

Group 4: diabetic rats Ren-2,

Group 5: diabetic rats Ren-2, the drug was administered, compound C, dose 1

Group 6: diabetic rats Ren-2, the drug was administered, compound A, dose 1

Group 7: diabetic rats Ren-2, the drug was administered, compound C, dose 2

Group 8: diabetic rats Ren-2, the drug was administered, compound A, dose 2

20 rats per group (160 rats)

a) Clinical parameters

Serial blood pressure measurements (4, 8, 12, 16 weeks), glycemic control (weekly), HbA1c level measurements (end parameter) and clinical parameters were evaluated at standard time intervals for testing on animal models.

b) Renal function (primary end parameters)

Serial measurements of renal function were carried out when determining creatinine and urea levels in plasma (using an autoanalyzer), albuminuria (radioimmunoassay analysis) and GFR (monopulse isotopic examination method) according to standard methods for animal testing.

c) The structure of the kidneys (secondary end parameters). The animals were killed (16 weeks after the development of diabetes), the left kidney was excised and fixed in formalin. The following morphological measurements were carried out:

Three micron-paraffin sections were shown with schiff-iodic acid, hematoxylin, eosin and Masson trichrome, and the obtained sections were examined by optical microscopy (OM) to measure glomerular volume, indices of glomerulosclerotic and tubulointerstitial pathological changes and heart hypertrophy. Immunohistochemical studies were performed using the analysis of "Avidin-Biotin" and was determined:

1. Collagen type I, III and IV to assess the degree of matrix deposition,

2. TGF-β and phospho-Smad 2 to assess the modulation of profibrotic growth factors and their activity.

The spatial distribution and quantitative determination of immunohistochemical parameters was evaluated by imaging, which allowed obtaining information about the type of cells and the localization of the development of the disease. To determine the state of the cell cycle, immunolocalization of TUNEL factor (apoptosis) and nuclear antigen of cell proliferation PCNA were used.

d) Molecular biology

The right kidney was quickly frozen in liquid nitrogen and used for molecular biological studies. Specific changes in tissues and cells can be evaluated using quantitative immunohistochemical image analysis and real-time PCR (ABI Prism 7700, Perkin Elmer Biosystem, Foster City, CA) using the TaqMan kit. The specified PCR analysis is known to specialists in this field of technology.

With the introduction of compound A, compound B or compound C intravenously in a dose of from 0.1 to 10 mg / kg, a favorable effect on complications after diabetes is observed.

B. Clinical trials

Clinical trials were performed by a double-blind randomized method in parallel groups with subjects suffering from type 2 diabetes mellitus, in which the disease could not be treated only with diet.

These trials included subjects diagnosed with type 2 diabetes mellitus, in which a normal glycemia level (HbA _1C less than 6.8%) is not achieved when dieting. The effect on glycemia levels with the administration of compounds A, B and C in this test was determined after 24 weeks, while a group of patients who were given a placebo was used as a control, and all patients followed a diet similar to the diet before the test. The measurement of glycemia was carried out according to marker end parameters established to control the treatment of diabetes. HbA _1C is the single most reliable parameter for controlling glycemia (see article D. Goldstein et al., Tests of Glycemia in Diadetes, Diabetes Care, vol. 18, No. 6, pp. 896-909 (1995)) and is the primary response parameter used in this test. Since the degree of glycosylation of hemoglobin depends on the concentration of glucose at the time of formation of each red blood cell, the level of HbAic allows you to estimate the average level of glucose in the blood for the previous three months.

Before starting double-blind treatment for 24 weeks, subjects were given a placebo for 4 weeks before breakfast, lunch and dinner (period I).

Subjects were then divided into 4 groups for double-blind studies for 24 weeks (period II), as shown in the table below:

Placebo ** Placebo * Compound A 10 mg * Compound A 10 mg ** * Introduction before breakfast, lunch and dinner ** Introduction only 1 time per day during breakfast

Approximately 100 subjects were randomized into each treatment group. The total test duration, including a preliminary period for each subject, was 28 weeks. Statistical analysis was performed using standard methods.

The subject was advised not to take the morning dose of the test drug or not to have breakfast on the day of the visit to the doctor according to the test schedule. The morning dose was administered by medical staff after fasting all samples for laboratory analysis and completion of all planned procedures. Medical visits according to the test schedule were prescribed at intervals of 2 weeks during period I, and at intervals of 4 to 8 weeks during period II. Subjects did not eat at least 7 hours before each visit to the doctor. All blood samples for laboratory tests were taken from 7:00 to 10:00 in the morning. All tests were performed according to Good Laboratory Practice guidelines according to standard procedures.

HbA _{1C was} measured using high performance liquid chromatography (HPLC) and ion exchange chromatography on a Bio-Rad Diamat analyzer. If peaks of altered forms of hemoglobin or degradation products of hemoglobin were observed in the chromatograms, then an additional affinity chromatography method was used.

The following parameters were also determined: fasting blood glucose (FPG), fasting lipid level (total lipids, HDL cholesterol (high density lipoprotein) and LDL (low density lipoprotein) and triglycerides), as well as body weight. FPG was determined using hexokinase, and LDL cholesterol was calculated using the Friedwald formula if the triglycerides were less than 400 mg / ml (4.5 mmol / L).

The various parameters described above for testing can be modified, for example, to optimize the doses of drugs for certain diseases or indications described in this context, due to tolerance problems during testing or to simplify the test method and obtain similar or identical results. For example, these clinical trials can be carried out with the participation of various populations of subjects, for example, subjects diagnosed with type 2 diabetes mellitus, in which the normoglycemia level (HbA _1C less than 6.8%) only when dieting, subjects suffering from other diseases, unlike diabetes mellitus, for example, other metabolic disorders, or subjects that were included in the tests according to other criteria, such as age or gender, you can also reduce the number of subjects, for example, from 70 to 100 subjects in the group, the duration of placebo administration period (period I) can also be changed, i.e. increase, decrease or exclude, the scheme of visits to the doctor can be increased, for example, every 10, 12 or 14 weeks, you can change the examination procedure when you visit the doctor, for example, the need to take blood samples for laboratory tests in the range from 7:00 to 10: 00 a.m., the HbA _1C level can be determined in another way, or one or more of the above parameters can be ruled out during testing, such as FPG or fasting lipid levels, or other parameters can be included (see below).

During the tests, other parameters can be determined, for example, using other analysis methods, which may include analysis of body fluids to quantify the parameters, such as described below, and which can be used, for example, to assess the tolerability of the active ingredients introduced: determination of hematocrit and hemoglobin , platelet count, red blood cell count, total and differential white blood cell count (basophils, eosinophils, lymphocytes, monocytes, segmented neutrophils and total neutrophils), definition of a bumin, alkaline phosphatase, alanine aminotransferase (serum glutamine pyruvate transaminase), aspartate aminotransferase (serum glutaminoxaloacetate transaminase), blood urea or blood urea, bicarbonate, calcium, chloride, and blood serum phosphate are elevated ( IBS), direct bilirubin, creatinine, γ-glutamyl transferase, lactate dehydrogenase, potassium, sodium, total bilirubin, total protein and uric acid in the blood, determination bilirubin, glucose, ketones, pH, protein in urine and urine density in subjects, determination of body weight, blood pressure (systolic and diastolic 3 minutes after sitting) and radial artery pulsation (3 minutes after sitting) .

The results of the studies indicate that compounds A, B and C can be used for prophylaxis and preferably for the treatment of type 2 diabetes mellitus and its complications.

According to the present invention, compounds A, B or C can be administered by any standard method, especially by the enteral route, for example, by the oral route, for example in the form of tablets or capsules, or by the parenteral route, for example, in the form of injectable solutions or suspensions, topically, for example in the form of lotions or gels, or in the nasal manner or in the form of suppositories.

Pharmaceutical compositions comprising compounds A, B or C in free form or in the form of pharmaceutically acceptable salts in combination with at least one pharmaceutically acceptable carrier or diluent are prepared according to standard procedures for admixing with a pharmaceutically acceptable carrier or diluent. Standard dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of the active substance.

The daily doses necessary for the implementation of the method of the present invention vary depending, for example, on the nature of the compound used, the organism of a particular subject, the method of administration, the severity of the condition intended for treatment. The daily dose for oral administration to large mammals, for example humans, is from about 0.5 mg to about 2000 mg of the active ingredient, for example, compounds A, B or C, which are administered in a standard manner, for example, in divided doses up to 4 times a day or slow release form.

Compound A or B, preferably compound A or a pharmaceutically acceptable salt thereof, is administered as a single ingredient or in combination with at least one active ingredient selected from the group consisting of:

(1) a PPAR agonist,

(2) compounds that increase HDL levels,

(3) antidiabetic agents, as indicated in this context,

(4) an antihypertensive agent,

(5) a cholesterol absorption modulator,

(6) apo-A1 analogues and mimetics,

(7) renin inhibitors,

(8) thrombin inhibitors,

(9) aldosterone inhibitors,

(10) GLP-1 agonists,

(11) glucagon receptor antagonists,

(12) cannabinoid receptor antagonists 1,

(13) anti-obesity agents,

(14) platelet aggregation inhibitors,

(15) DPP-IV inhibitors, and

(16) prosclerotic growth factors

or in each case, in the form of their pharmaceutically acceptable salts and optionally in admixture with a pharmaceutically acceptable carrier.

In a preferred embodiment of the present invention, compound C or a pharmaceutically acceptable salt thereof is administered in combination with at least one active ingredient selected from the group consisting of:

(1) compounds that increase HDL levels,

(2) an antihypertensive agent,

(3) a cholesterol absorption modulator,

(4) analogues and mimetics of apo-A1,

(5) renin inhibitors,

(6) thrombin inhibitors,

(7) aldosterone inhibitors,

(8) glucagon receptor antagonists,

(9) cannabinoid receptor antagonists 1,

(10) anti-obesity agents,

(11) platelet aggregation inhibitors,

(12) DPP-IV inhibitors, and

(13) prosclerotic growth factors

or in each case in the form of their pharmaceutically acceptable salts and optionally in admixture with a pharmaceutically acceptable carrier.

The term "PPAR agonists" means, without limitation, the selective α-agonists of PPAR, γ-agonists of PPAR or δ-agonists of PPAR or double α / γ agonists and double α / δ agonists.

Selective PPAR α agonists include those described in US 2005/32224, published March 16, 2006, Publication No. WO 06/029349.

Double acting PPAR α / γ agonists include those described in PCT / EP 02/13025, published May 30, 2003, Publication No. WO 03/043985, especially Compound 19 described in Example 4 (Compound 4-19)

Antidiabetic compounds include PPAR δ compounds, insulin sensitivity enhancers that restore impaired insulin receptor function in order to reduce insulin resistance and accordingly increase insulin sensitivity.

Examples of δ-compounds of PPAR include compounds of the formula:

и

and

A suitable insulin sensitivity enhancer is, for example, the corresponding hypoglycemic derivative of thiazolidinedione (glitazone).

The corresponding glitazone is, for example, (S) - ((3,4-dihydro-2- (phenylmethyl) -2H-1-benzopyran-6-yl) methylthiazolidine-2,4-dione (englitazone), 5 - {[4 - (3- (5-methyl-2-phenyl-4-oxazolyl) -1-oxopropyl) phenyl] methyl} thiazolidin-2,4-dione (darglitazone), 5 - {[4- (1-methylcyclohexyl) methoxy) phenyl] methyl} thiazolidine-2,4-dione (ciglitazone), 5 - {[4- (2- (1-indolyl) ethoxy) phenyl] methyl} thiazolidine-2,4-dione (product DRF2189), 5- { 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy)] benzyl} thiazolidine-2,4-dione (product BM-13.1246), 5- (2-naphthylsulfonyl) thiazolidine-2,4- dione (product AY-31637), bis {4 - [(2,4-dioxo-5-thiazolidinyl) methyl] phenyl} methane (pr product YM268), 5- {4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-hydroxyethoxy] benzyl} thiazolidine-2,4-dione (product AD-5075), 5- [4 - (1-phenyl-1-cyclopropanecarbonylamino) benzyl] thiazolidine-2,4-dione (product DN-108), 5 - {[4- (2- (2,3-dihydroindol-1-yl) ethoxy) phenyl] methyl} thiazolidine-2,4-dione, 5- [3- (4-chlorophenyl]) - 2-propynyl] -5-phenylsulfonyl) thiazolidine-2,4-dione, 5- [3- (4-chlorophenyl]) -2-propynyl] -5- (4-fluorophenylsulfonyl) thiazolidine-2,4-dione, 5 - {[4- (2- (methyl-2-pyridinylamino) ethoxy) phenyl] methyl} thiazolidine-2,4-dione (rosiglitazone), 5 - {[4- (2- (5-ethyl-2-pyridyl) ethoxy) phenyl] methyl} thiazolidine-2,4-dione (pioglitazone), 5 - {[4 - ((3,4 dihydro-6-hydro si-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) phenyl] methyl} thiazolidin-2,4-dione (troglitazone), 5- [6- (2-fluorobenzyloxy) naphthalene -2-ylmethyl] thiazolidin-2,4-dione (product MCC555), 5 - {[2- (2-naphthyl) benzoxazol-5-yl] methyl} thiazolidin-2,4-dione (product T-174) and 5- (2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy-N- (4-trifluoromethylbenzyl) benzamide (product KRP297). Pioglitazone, rosiglitazone and troglitazone are preferred.

Antidiabetic agents include non-glitazone-type PPAR γ agonists, especially N- (2-benzoylphenyl) -L-tyrosine analogues, for example, product GI-262570 and JTT501.

Antihypertensive agents include angiotensin converting enzyme inhibitors (ACE inhibitors), renin inhibitors, calcium channel blockers, diuretics, β-blockers, inhibitors of neutral endopeptidase (NEP inhibitors), inhibitors endotelinkonvertiruyuschego enzyme (= ECE inhibitors) and angiotensin II antagonists (AT ₁₎ optionally in combination with a diuretic, for example Co-Diovan®. Suspension of the enzymatic degradation of angiotesin I to angiotensin II in the presence of ACF inhibitors is a promising way to regulate blood pressure, and thus is a promising approach to the treatment of congestive heart failure.

The class of ACF inhibitors includes compounds of various structures. For example, this class includes compounds that are selected from the group consisting of alaceptril (as described in EP 7477), benazepril (as described in EP 72352), benazeprilat (as described in EP 72352), captopril (as described in US patent 4105776), ceronapril (as described in EP 229520), cilazaril (as described in EP 94095), delapril (as described in EP 51391), enalapril (as described in EP 12401), enaprilat (as described in EP 12401), fosinopril (as described in patent EP 53902), imidapril (as described in patent EP 95163), lisinopril (as opi ano in patent EP 12401), moveltipril (as described in patent ZA 82/3779), perindopril (as described in patent EP 49658), hinapril (as described in patent EP 49605), ramipril (as described in patent EP 79022), spirapril (as described in EP 50800), temocapril (as described in EP 161801), trandolapril (as described in EP 551927) and moexipril, or in each case their pharmaceutically acceptable salts.

Preferred ACF inhibitors are commercial preparations, most preferred are benazepril and enalapril.

The present invention also provides the corresponding stereoisomers and the corresponding crystalline hydrates, for example, solvates and polymorphic forms, which are described in this context, and, if possible, all pharmaceutically acceptable salts of these compounds.

Compounds intended for combination may be used as pharmaceutically acceptable salts. If such compounds contain, for example, at least one basic group, then they can form acid addition salts. Appropriate acid addition salts can be prepared, if necessary, if the compounds contain another additional basic group. Compounds containing an acid group (e.g. COOH) can also form salts with bases.

The AT ₁ receptor antagonist class includes compounds of various structures, most preferably of a non-peptide nature. Examples of such compounds include compounds that are selected from the group consisting of valsartan (as described in patent EP 443983), losartan (as described in patent EP 253310), candesartan (as described in patent 459136), eprosartan (as described in patent EP 403159) , irbesartan (as described in patent EP 454511), olmesartan (as described in patent EP 503785), tazosartan (as described in patent EP 539086), telmisartan (as described in patent EP 522314), compound E-4177 of the formula

compound SC-52458 of the formula

compound ZD-8731 of the formula

or in each case their pharmaceutically acceptable salts.

Preferred AT ₁ receptor antagonists are commercial products, most preferred are Diovan® and Co-Diovan® products or pharmaceutically acceptable salts thereof.

The class of calcium channel blockers (CCBs) preferably includes dihydropyridines (DHPs) and compounds of a different structure, such as CCCs such as diltiazem and verapamil

The CCLs used in this combination are preferably DHP derivatives that are selected from the group consisting of amlodipine, felodipine, riosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nizoldipine, nitrendipine and nivalidipine, preferably which are selected from the group consisting of flunarizine, prenylamine, diltiazem, fendilin, gallopamil, mibefradil, anipamil, thiapamil and verapamil, and in each case, pharmaceutically acceptable salts of these compounds. All of these CCLs are used for treatment, for example, as antihypertensive, anti-stenocardial and anti-arrhythmic drugs.

Preferred BCCs include amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nizoldipine, nitrendipine and verapamil, or, depending on the specific BCC, their pharmaceutically acceptable salts. The most preferred DHP derivative is amlodipine or a pharmaceutically acceptable salt thereof, especially beylate. The most preferred derivative of a different structure is verapamil or a pharmaceutically acceptable salt thereof, especially its hydrochloride salt.

A diuretic is, for example, a thiazide derivative that is selected from the group consisting of chlortiazide, hydrochlorothiazide, methylchlorothiazide, amiloride, triamteren and chlortalidone. Most preferred is hydrochlorothiazide.

β-Blockers suitable for use in the present invention include β-adrenergic blocking agents (β-blockers) that compete with epinephrine for binding to β-adrenergic receptors and affect the action of epinephrine. Preferred β-blockers are selective for the β-adrenergic receptor compared to α-adrenergic receptors and thus do not have a significant α-blocking effect. Suitable β-blockers include compounds that are selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, cartolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and tim. If the β-blocker is an acidic or basic compound or otherwise forms pharmaceutically acceptable salts or prodrugs, such forms are included within the scope of the present invention, and it should be understood that the compounds can be administered in free form or in the form of a pharmaceutically acceptable salt or prodrug, such as hydrolyzable under physiological conditions and an acceptable ester. For example, metoprolol is usually administered in the form of tartrate, propanolol is administered in the form of hydrochloride, and the like.

The NEP inhibitors of the present invention include the compounds described in US Pat. Nos. 5,223,516 and 4,610,816, incorporated herein by reference, in particular N- [N- [1 (S) -carboxy-3-phenylpropyl] - (S) - phenylalanyl) - (S) -isoserine and N- [N - [((1S) -carboxy-2-phenyl) ethyl] - (S) -phenylalanyl-β-alanine, the compounds described in US patent No. 4929641, especially N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propionyl] methionine, compound SQ 28603 (N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] -β-alanine) described in South African Patent Application 84/0670, Compound UK 69578 (cis-4 - [[[1- [2-carboxy-3- (2-metho sietoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid) and its active enantiomer (s), thiorphan and its enantiomers, retrotiorphan, phosphoramidone and compound SQ 29072 (7 - [[2- (mercaptomethyl) -1-oxo-3- phenylpropyl] amino] heptanoic acid). Also suitable are any prodrug forms of the above NEP inhibitors, for example, compounds in which one or more carboxyl groups are esterified.

The NEP inhibitors of the present invention also include compounds described in US Pat. No. 5,217,996, in particular N- (3-carboxy-1-oxopropyl) - (4S) -paraphenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester, the compounds described in EP 00342850, especially (S) -cis-4- [1- [2- (5-indanyloxycarbonyl) -3- (2-methoxyethoxy) propyl] -1-cyclopentanecarboxamido] -1-cyclohexanecarboxylic acid, the compounds described in GB 02218983, especially 3- (1- [6-endo-hydroxymethylbicyclo [2.2.1] heptane-2-exo-carbamoyl] cyclopentyl) -2- (2-methoxyethyl) propanoic acid, The phenomena described in WO 92/14706, in particular N- (1- (3- (N-tert-butoxycarbonyl- (S) -prolyamino) -2 (S) -tert-butoxycarbonylpropyl) cyclopentanecarbonyl) -O- methyl ester benzyl- (S) -serine, compounds described in patent EP 00343911, compounds described in patent JP 06234754, compounds described in patent EP, 00361365, especially 4 - [[2- (mercaptomethyl) -1-oxo-3 -phenylpropyl] amino] benzoic acid, the compounds described in WO 90/09374, in particular 3- [1- (cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl) cyclopentyl] -28- ( 2-methoxyethoxymethyl) propanoic acid, soy tendency described in JP 07157459, especially N - ((2S) -2- (4-biphenylmethyl) -4-carboxy-5-phenylvaleryl) glycine, compounds described in WO 94/15908, especially 1N- ( 1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) -L-phenylalanine, compounds described in US Pat. No. 5,273,990, especially (S) - (2-biphenyl-4-yl) -1- (1H-tetrazol-5-yl) ethylamino) methylphosphonic acid, the compounds described in U.S. Pat. No. 5294632, especially (S) -5- (N- (2- (phosphonomethylamino) -3- (4-biphenyl) propionyl) -2-aminoethyl) tetrazole, the compounds described in U.S. Pat. No. 5250522, especially 3- [1,1'-biphenyl] -4-yl-H- [diphenoxyphosphinyl) methyl] -L-alanyl-β-alanine, the compounds described in patent EP 00636621, especially N- ( 2-carboxy-4-thienyl) -3-mercapto-2-benzylpropanamide, the compounds described in WO 93/09101, especially 2- (2-mercaptomethyl-S-phenylpropionamido) thiazol-4-ylcarboxylic acid, the compounds described EP 00590442, in particular ((L) - (I - ((2,2-dimethyl-1,3-dioxolan-4-yl) methoxy) carbonyl) -2-phenylmethyl) -L-phenylalanyl) -β- alanine, N- [N - [(L) - [1 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] - (R ) -alanine, N- [N - [(L) -1-car hydroxy-2-phenylethyl] -L-phenylalanyl] - (R) -alanine, ethyl N- [2-acetylthiomethyl-3- (2-methylphenyl) propionyl] methionine, N- [2-mercaptomethyl-3- (2- methylphenyl) propionyl] methionine, N- [2 (S) -mercaptomethyl-3- (2-methylphenyl) propanoyl] - (S) -isoserine, N- (S) - [3-mercapto-2- (2-methylphenyl) propionyl] - (S) -2-methoxy- (R) -alanine, N- [1 - [[1- (S) -benzyloxycarbonyl-3-phenylpropyl] amino] cyclopentylcarbonyl] - (S) -isoserine, N- [ 1 - [[1- (S) -carbonyl-3-phenylpropyl] amino] cyclopentylcarbonyl] - (S) -isoserine, 1,1 '- [dithiobis- [2 (8) - (2-methylbenzyl) -1-oxo -3,1-propanediyl]] - bis- (S) -isoserine, 1,1 '- [dithiobis- [2 (S) - (2-methylbenzyl) -1-oxo-3,1-propanediyl ]] - bis- (S) -methionine, N- (3-phenyl-2- (mercaptomethyl) propionyl) - (S) -4- (methyl mercapto) methionine, N- [2-acetylthiomethyl-3-phenylpropionyl] -3 aminobenzoic acid, N- [2-mercaptomethyl-3-phenylpropionyl] -3-aminobenzoic acid, N- [1- (2-carboxy-4-phenylbutyl) cyclopentanecarbonyl] - (S) -isoserine, ethyl N- [1 - (acetylthiomethyl) cyclopentanecarbonyl] - (S) -methionine, 3 (S) - [2- (acetylthiomethyl) -S-phenylpropionyl] amino-ε-caprolactam and the compounds described in application WO 93/10773,

in particular N- (2-acetylthiomethyl-3- (2-methylphenyl) propionyl) methionine ethyl ester.

ECF inhibitors include the compound SLV306.

Apo-A1 analogs and mimetics include the 18-membered peptide D4F, sequence ID No. 5 (US patent No. 6664230, filed December 16, 2003).

Renin inhibitors include, for example, peptide renin inhibitors, and preferably non-peptide renin inhibitors.

Non-peptidic renin inhibitors include, for example, ditykiren, terlakiren, zankiren, compound SPP-100, or a compound of the formula:

or, in each case, pharmaceutically acceptable salts of these compounds.

Renin inhibitor of formula (I) (2 (S), 4 (S), 5 (S), 7 (S) -N- (3-amino-2,2-dimethyl-3-oxopropyl) -2,7-di (1-Methylethyl) -4-hydroxy-5-amino-8- [4-methoxy-3- (3-methoxypropoxy) phenyl] octanamide) is described in patent EP 678503 A. Most preferred is its hemi-fumarate.

Non-peptide renin inhibitors include the compounds described in WO 97/09311, in particular the renin inhibitors described in the claims and examples, in particular the compound SPP100 of the formula

First of all, the compounds RO 66-1132 and RO-66-1168 formulas:

и

and

accordingly, described in the application WO 04/002957, especially the renin inhibitors described in the claims and examples. Relevant objects described in these WO applications are incorporated herein by reference.

Cholesterol absorption modulators include Zetia® and KT6-971 (Kotobuki Pharmaceutical Co., Japan).

Thrombin inhibitors include Astra Zeneca's Ximelagatran (Exanta®) as described in WO 97/23499 published October 12, 1999.

Aldosterone inhibitors include compounds of various structures. GLP-1 agonists include GLP-1 analogs, GLP-1 receptor agonists, and protein G-associated receptor 120 agonists (GPR120). Examples of GLP-1 analogues include the product Exendin-4 ^™ (exenatide) or compound LY315902, as described by Myers SR et al., Annual Meeting and Scientific Sessions of the American Diabetes Association, 58: Chicago (Abs 0748) (1998), and compound LY307161, as described in Trautman M. et al., Diabetologia, vol. 43, issue 1, s.A146 (2000). GPR120 agonists include free-form fatty acids as described in Hirasawa A. et al., Nature Medicine, Vol. 11, No. 1 (2005).

Glucagon receptor antagonism includes the incorporation of antisense molecules, e.g., RNA and oligonucleotides, into the gene encoding the glucagon receptor, and glucagon receptor antagonists, such as, for example, low molecular weight antagonists that bind to the glucagon receptor and prevent or inhibit the binding of natural ligands. Antisense technology is described in the art. Some antisense oligonucleotides (ASOs) and methods for identifying ASOs are described in the article by K. Sloop et al., The Journal of Clinical Investigation, Vol. 113, No. 11 (2004), the entire contents of which are incorporated herein by reference.

Antagonists of cannabinoid receptor 1 (cb1) include, without limitation, the compounds described in patent application US 2005/32224, published March 16, 2006 (publication No. WO 06/029349, compounds of formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih).

Anti-obesity agents include Xenical®, Meridia®, and cannabinoid receptor antagonists.

Platelet aggregation inhibitors include Plavix®, Aspirin, and Clopidgrel®.

Prosclerotic growth factors include transforming growth factor β 1 (TGF β).

HDL-enhancing compounds include, but are not limited to, cholesterol ester transfer protein inhibitors (CETP inhibitors). Examples of CETP inhibitors include compound JTT705 described in US patent No. 6426365 published July 30, 2002 (example 26), and its pharmaceutically acceptable salts.

DPP-IV inhibitors are compounds of peptide and non-peptide nature.

DPP-IV inhibitors in each case are mainly and in detail described in documents WO 98/19998, DE 19616486 A1, WO 00/34241, WO 95/15309 and WO 01/52825, especially in the claims related to the compounds described in the examples (final products), while the object of the final products, pharmaceuticals and claims are included in the present invention in the form of links to these publications. Compounds DPP728 and LAF237 are described in detail in WO 98/19998 (Example 3) and in WO 00/34241 (Example 1), respectively. The DPP-IV inhibitor is described in detail in Diabetes, Vol. 47, pp. 1253-1258 (1998).

The structure of active agents, which can be identified by common or trade names, is described in the latest edition of The Merck Index or in the Physician's Desk Reference or in databases, such as the Patents International database (such as IMS World Publications) or Current Drugs The relevant content of these sources is incorporated into this description by reference. A person skilled in the art can identify active agents and, using the references indicated in this context, can obtain and evaluate pharmaceutical properties using standard in vitro and in vivo methods.

If compound A, B, C or their salt is administered in combination with other drugs, the doses of the co-administered compound vary depending on the nature of the co-drug, the condition intended for treatment, and the like. The terms “coadministration” or “administration in combination” used in this context mean the administration of the selected therapeutic agents to one patient, as well as courses of treatment in which the agents are not necessarily administered in the same way or simultaneously.

The present invention also provides the following objects:

5.1. A pharmaceutical combination comprising a) a first agent, which is compound A or compound B or a pharmaceutically acceptable salt thereof, preferably compound A or its acetate, and b) a co-administered agent, for example a second drug agent, as described above, for example a drug agent, which selected from the group comprising a compound that increases HDL, δ-PPAR, a non-glitazone-type γ-PPAR agonist, an antihypertensive agent, a cholesterol absorption modulator, an apo-A1 analog or mimetic, a renin inhibitor, a thrombin inhibitor , an aldosterone inhibitor, a GLP-1 agonist, a glucagon receptor antagonist, a cannabinoid receptor antagonist 1, an anti-obesity agent, a platelet aggregation inhibitor, a PPAR agonist, a prosclerotic growth factor, or pharmaceutically acceptable salts of these compounds.

5.2. A pharmaceutical combination comprising a) a first agent, which is compound C or a pharmaceutically acceptable salt thereof, for example its acetate, and b) a co-administered agent, for example a second drug agent, as described above, for example, a drug agent selected from the group consisting of a compound HDL-increasing, antihypertensive agent, cholesterol absorption modulator, analog or mimetic apo-A1, renin inhibitor, thrombin inhibitor, aldosterone inhibitor, glucagon receptor antagonist, cann antagonist inoidnogo 1 receptor, anti-obesity agent, a platelet aggregation inhibitor, prosklerotichesky growth factor or a pharmaceutically acceptable salt thereof.

6. A method of treating, preventing or slowing the development of diabetes or complications caused by diabetes, as described herein, for example, for treating, preventing or slowing the development of diabetic nephropathy, diabetic cardiomyopathy or diabetic neuropathy, which consists in co-administration, for example, simultaneously or sequentially, a therapeutically effective amount of compound A, B or C, or a pharmaceutically acceptable salt thereof, and a second drug, for example, as described above.

7.1. A method of treating, preventing diabetes or complications caused by diabetes, as described in this context, or slowing their development, which consists in the introduction to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical combination comprising compound A, B or C or their pharmaceutically acceptable salts, preferably compound A or its acetate, and b) a co-administered agent that is selected from the group consisting of:

(1) a PPAR agonist,

(2) compounds that increase HDL levels,

(3) antidiabetic agents, as indicated in this context,

(4) an antihypertensive agent,

(5) a cholesterol absorption modulator,

(6) analogues and mimetics apo-A1,

(7) renin inhibitors,

(8) thrombin inhibitors,

(9) aldosterone inhibitors,

(10) GLP-1 agonists,

(11) glucagon receptor antagonists,

(12) cannabinoid receptor antagonists 1,

(13) anti-obesity agents,

(14) platelet aggregation inhibitors,

(15) DPP-IV inhibitors, and

(16) prosclerotic growth factors

or in each case their pharmaceutically acceptable salts and optionally a pharmaceutically acceptable carrier.

7.2. A method of treating, preventing diabetes or complications caused by diabetes, as described in this context, or slowing their development, for example, for treating, preventing or slowing the development of diabetic nephropathy, diabetic cardiomyopathy or diabetic neuropathy, preferably diabetic nephropathy, which is the introduction of a patient in need in such treatment, a therapeutically effective amount of the pharmaceutical combination described in paragraph 5.1. or 5.2.

With the introduction of the pharmaceutical combination of the present invention, a beneficial effect is observed, especially a synergistic effect. For example, with combined treatment, an unexpected increase in the duration of action, a decrease in side effects, a decrease in the doses of individual drugs, or an improvement in the quality of life compared with monotherapy can be observed. Another advantage is that lower doses of the active ingredients can be used as part of the combination of the present invention, for example, not only lower doses can be used, but also the frequency of administration of the drug can be reduced, as well as the likelihood of side effects. The above advantages correspond to the requirements or wishes of patients undergoing treatment.

The combinations of the present invention, as described in this context, can be used for simultaneous or sequential administration in any order, for example for separate use or for use as a fixed combination.

Combinations of the present invention include “component sets”, in the sense that both agents a) and b) can be administered independently or using various fixed combinations containing specific amounts of components at different points in time. The components of the “kit” can, for example, be entered simultaneously or alternately, i.e. at different points in time with the same or different time intervals for each component of the "set". Preferred time intervals are chosen so that when the combination is administered, an increased effectiveness of the action on the disease or condition that is intended for treatment is observed, compared with the action of each of the components individually.

The effective dose of each component of the combination of the present invention varies depending on the nature of the particular compound or pharmaceutical composition, route of administration, condition intended for treatment, severity of the condition intended for treatment. Thus, the dose values of the combinations of the present invention are selected based on a number of factors, including the route of administration. The therapist, attending physician or veterinarian can determine and prescribe the effective amount of the individual active ingredients necessary to reduce the intensity of the symptoms, slow the development or suppress the condition. When selecting the optimal doses that provide the necessary concentration of active ingredients in the range at which efficacy without toxicity is manifested, it is necessary to take into account the kinetics of delivery of the active ingredients to the target sites.

The daily doses of agent a) or agent b) vary depending on a number of factors, for example, the nature of the selected compound, the particular condition to be treated, and the desired effect. However, generally satisfactory results are achieved with the administration of agent a) in a daily dose of from about 0.1 to about 100 mg / kg daily in a single dose or in divided doses.

The approximate daily dose of the PPAR agonist is from about 1 mg to 360 mg, the more preferred daily dose is from 1 mg to 100 mg, most preferably from 1 mg to 50 mg, for example, for a patient weighing about 75 kg. Preferred dosage forms of ACF inhibitors are, for example, tablets or capsules comprising, for example, from about 5 mg to about 20 mg, preferably 5 mg, 10 mg, 20 mg or 40 mg of benazepril, from about 6.5 mg to 100 mg preferably 6.25 mg, 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg of captopril, from about 2.5 mg to about 20 mg, preferably 2.5 mg, 5 mg, 10 mg or 20 mg enalapril, from about 10 mg to about 20 mg, preferably 10 mg or 20 mg of fosinopril, from about 2.5 mg to about 4 mg, preferably 2 mg or 4 mg of perindopril, from about 5 mg to about 20 mg, preferably 5 mg, 10 mg or 20 mg of quinapril, or from about 1.25 mg to about 5 mg, preferably 1.25 mg, 2 5 mg or 5 mg ramipril. The preferred frequency of administration is 3 times a day.

A preferred combination is a combination of compound A, preferably in the form of an acetate, and an ACF inhibitor, for example, as described above.

Claims (8)

1. The use of 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione or its pharmaceutically acceptable salts for the preparation of a medicament an agent intended to treat, prevent, or delay the development of diabetes-related complications. 2. The use according to claim 1, where the complication is nephropathy, neuropathy or cardiomyopathy. 3. The use according to claim 1 or 2, wherein the compound is 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrol-2 acetate, 5-dione. 4. A method of treating or preventing diabetic nephropathy, neuropathy or cardiomyopathy, or slowing their development, which consists in the introduction of an effective amount of 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione or its pharmaceutically acceptable salts to a subject in need of such treatment. 5. A pharmaceutical composition for treating or preventing diabetes-related complications, and comprising 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole -2,5-dione or its pharmaceutically acceptable salts in a mixture with one or more pharmaceutically acceptable diluents or carriers, where the complication is selected from nephropathy, neuropathy or cardiomyopathy. 6. A pharmaceutical combination comprising a) a first agent selected from 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrol-2, 5-dione or its pharmaceutically acceptable salts, and b) at least one active ingredient selected from the group consisting of HDL-enhancing compound, δ-PPAR compound, non-glitazone-type γ-PPAR agonist, antihypertensive agent, cholesterol absorption modulator, analog or mimetic apo-A1, renin inhibitor, thrombin inhibitor, aldosterone inhibitor, GLP-1 agonist, glucagon antagonist th receptor antagonist, a cannabinoid receptor 1, antiobesity agent, platelet aggregation inhibitor, a PPAR agonist type prosklerotichesky growth factor or their pharmaceutically acceptable salts. 7. The combination according to claim 6, where the first agent is 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5- dion or its acetate. 8. A method of treating or preventing diabetes or complications caused by diabetes, or slowing their development, which consists in the joint introduction, for example, simultaneously or sequentially, of a therapeutically effective amount of 3- (1H-indol-3-yl) -4- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] pyrrole-2,5-dione or its pharmaceutically acceptable salts, and a second drug, to a subject in need of such treatment, where the second drug is selected from the group comprising the compound anti-diabetic increasing HDL agent, antihypertensive agent, cholesterol absorption modulator, apo-A1 analog or mimetic, renin inhibitor, thrombin inhibitor, aldosterone inhibitor, GLP-1 agonist, glucagon receptor antagonist, cannabinoid receptor antagonist 1, anti-obesity agent, agregator inhibitor, DPP-IV inhibitor, prosclerotic growth factor, or pharmaceutically acceptable salts thereof.